Acute myeloid leukemia (AML) is one of the most aggressive hematological malignancies that despite recent progresses remains an unmet medical need. Genetic markers are used to define different disease categories and prognostic groups. One of the most frequent is mutations in the Fms-like tyrosine kinase 3 (FLT3) gene, particularly internal tandem duplication (ITD). FLT3-ITD represents an important adverse risk factor, and although targetable with specific approved inhibitors that are routinely used worldwide, it mostly requires allogeneic hematopoietic stem cell transplant to give patients prospective of cure. FLT3-ITD represents specifically the ‘tip of the balance’ for the prognostic definition of a particular leukemia that is the AML with nucleophosmin (NPM1) gene mutation, the most frequent AML, accounting for about one-third of cases. Indeed, only when in absence of FLT3-ITD (FLT3-ITDneg), patients with NPM1 mutations are regarded as favorable outcome with standard chemotherapy alone. Yet a significant proportion - up to about 40% - of these patients will relapse, and notably, about 20-30% undergo relapse with emergence of mutations, including FLT3-ITD, originally not detected at diagnosis by standard approaches.
We previously found that single FLT3-ITDpos cells at either diagnosis or during treatment can be clinically relevant as they acquire drug resistance, may emerge after therapy and initiate relapse in patients otherwise regarded as FLT3-ITDneg and thus at favorable risk at presentation. The solution would be to intercept these cells earlier and adapt targeted therapy in order to prevent relapse. In our PoC study, we validated our hypothesis in patients and provided data that revealed the value of single FLT3-ITDpos cells as novel biomarker to re-define prognosis, and possibly refine treatment strategy, in the specific setting of NPM1-mutated AML.
Biomarkers are specific characteristics of a disease that can be measured and evaluated in an objective manner. FLT3-ITD has the characteristics of diagnostic, prognostic ad predictive biomarker. Therefore, studies on FLT3-ITD as biomarker are complex because of the different implications, but at the same time may have a great impact. The aim of this project was to develop a reliable assay that can be translated into the clinics, and address clinical issues since it requires validation in clinical studies involving patients. The final idea is that every new case of AML with mutated NPM1 and FLT3 wild-type according to standard-of-care would need to be tested with the novel approach to be assigned to the correct risk category and adapt targeted therapy. The gain would be to bring new knowledge for AML management. The impact would be tremendous at different levels, leading to
1) refinement in definition of prognostic risk categories in AML;
2) change in the diagnostic flow-chart and guideline for AML;
3) adoption of the concept of adaptive therapy in AML based on the demonstrated predictive value of the new biomarker.
This project is ground breaking as it could change prognostic risk parameters and the paradigm of treatment in AML by shifting the concept of biomarker and therapeutic target to the single-cell level, and precision therapy to adaptive treatment strategy.
Patients will highly benefit from the results of this project, since their assignment to the correct risk category will allow them to have access to targeted therapy and start, since the beginning, the correct therapeutic path preventing relapses. Industries would benefit from the development and commercialization of the newly developed diagnostic tool as well as from the extended use of the specific drug.
